EP0003474B1 - Verfahren zur Prothrombin-Bestimmung, dazu verwendetes Reagenz und Verfahren zur Herstellung eines Faktor-Xa-Präparats - Google Patents
Verfahren zur Prothrombin-Bestimmung, dazu verwendetes Reagenz und Verfahren zur Herstellung eines Faktor-Xa-Präparats Download PDFInfo
- Publication number
- EP0003474B1 EP0003474B1 EP78101680A EP78101680A EP0003474B1 EP 0003474 B1 EP0003474 B1 EP 0003474B1 EP 78101680 A EP78101680 A EP 78101680A EP 78101680 A EP78101680 A EP 78101680A EP 0003474 B1 EP0003474 B1 EP 0003474B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- factor
- prothrombin
- pna
- arg
- determination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2337/00—N-linked chromogens for determinations of peptidases and proteinases
- C12Q2337/10—Anilides
- C12Q2337/12—Para-Nitroanilides p-NA
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/4609—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates from reptiles
- G01N2333/4613—Snake venom
- G01N2333/4616—Snake venom from Russell's viper
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/4609—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates from reptiles
- G01N2333/4613—Snake venom
- G01N2333/4633—Snake venom from Echis carinatus; Ecarin
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
- G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
- G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
- G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
- G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
- G01N2333/96433—Serine endopeptidases (3.4.21)
- G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
- G01N2333/96444—Factor X (3.4.21.6)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/90—Enzymes; Proenzymes
- G01N2333/914—Hydrolases (3)
- G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
- G01N2333/974—Thrombin
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2405/00—Assays, e.g. immunoassays or enzyme assays, involving lipids
- G01N2405/04—Phospholipids, i.e. phosphoglycerides
Definitions
- the invention relates to a method and a reagent for prothrombin determination in biological material, such as. B. Blood plasma.
- the determination of the prothrombin level is an important clinical parameter for the monitoring of the course of anticoagulant therapy.
- the detection of a factor II deficiency, which is both congenital and acquired, is equally important.
- H. can be the result of a primary underlying disease.
- Staphylocoagulase and snake venom were also used as activators. You activate prothrombin directly. However, it has been shown that these poisons also activate PIVKA prothrombin (PIVKA is a short name for protein induced by vitamin K absence; a synonym is decarboxyprothrombin), which forms during treatment with oral anticoagulants. Staphylocoagulase also converts this so-called PIVKA prothrombin.
- the object of the invention is therefore to create a method and a reagent for the determination of prothrombin in biological material, such as blood plasma, which enable a test with fewer sources of error, increased precision, sensitivity and better reproducibility.
- biological material such as blood plasma
- Such a test should be specific, i. H. only record prothrombin and not also PIVKA prothrombin. All prothrombin should be converted quickly and completely into thrombin without the activator required for this taking part in the color reaction in any form.
- a method for the determination of prothrombin in biological material by conversion into thrombin, enzymatic cleavage of a thrombin substrate with the thrombin and measurement of a cleavage product, characterized in that factor Xa for the biological material to be examined, preferably human factor Xa is added.
- factor Xa for the biological material to be examined, preferably human factor Xa is added.
- the human factor Xa has proven to be the most suitable. But it is also z. B. the use of bovine factor Xa possible.
- the yellow color of the free p-nitroaniline can be measured photometrically at about 390 to 410 nm, the amount of dye released per unit of time being proportional to the enzyme activity.
- Tris and / or imidazole buffers of about pH 8-9, to which hydrochloric acid and / or sodium chloride are optionally added, are preferred as buffers.
- Phospholipids and calcium chloride are used as co-reagents for activating the prothrombin.
- the substrate is added after the prothrombin has been converted completely to thrombin in the test solution after adding factor Xa.
- the factor Xa according to the invention is easily accessible through a simple extraction process, which is also the subject of the invention.
- This process is characterized in that plasma, preferably human plasma, is treated with a prothombin activator, a protein adsorbent is added after centrifugation, the precipitate is eluted with protein eluent and the eluate is treated with a factor X activator and optionally a soluble calcium salt.
- Echis carinatus venom as a prothrombin activator, but snake venoms such as Taipan snake venom (Oxyuranus scutellatus) and trypsin are also suitable.
- the clot obtained after the treatment with the prothrombin activator, which is centrifuged off, consists partly of fibrinogen, antithrombin and thrombin.
- Barium sulfate, citrate and oxalate are preferred as protein adsorbent, but aluminum hydroxide, DEAE-Sephadex and QAE-Sephadex are also suitable; an aqueous trisodium citrate solution, phosphate buffer or sodium chloride can be used as protein eluents Solution can be used.
- Russel's viper venom is particularly suitable as a factor X activator.
- Calcium chloride is preferred as the soluble calcium salt.
- Additional steps can be added to achieve a highly purified factor Xa.
- These further purification steps can consist of gel filtration with a molecular sieve that differentiates the range from 50,000-100,000, e.g. B. Sephadex @ G 100, Biogel @ P 100, which can be eluted with sodium acetate buffer (0.4 m, pH 7).
- Ammonium sulfate precipitation e.g. 45 to 55% solution, pH 6-8), ion exchange chromatography with DEAE-Sephadex @ A 50, DEAE cellulose or QAE-Sephadex @ / cellulose, with Na / as a buffer K-phosphate (e.g.
- the highly purified factor Xa can be used in the test, in the form of a solution, e.g. B. in veronal or Michaelis buffer, in physiological saline and in the test buffer. However, this cleaning step can be dispensed with for use in the test according to the invention and the factor Xa preparation enriched as described above can be used.
- DE-OS 26 54 189 describes a method for producing a factor Xa preparation.
- the method according to the invention cannot be derived from this without inventive step.
- the process described there gives no indication of removal of the prothrombin (factor 11) at a specific point in the production process; this method leads to a preparation which, in addition to factor X, also contains factor II.
- the surprising improvement in the process according to the invention is that the factor Ila (thrombin) formed before the barium sulfate precipitation is not bound to the barium sulfate, that is to say it is already separated from the factor X here, while the opposite is the case with the factor 11.
- the process according to the invention thus has the advantage over the process of DE-OS 26 54 189 that a largely pure factor X preparation is obtained in one step (barium sulfate adsorption).
- the invention furthermore relates to a reagent for determining prothrombin, comprising a thrombin substrate and a prothrombin activator, characterized in that the prothrombin activator is factor Xa, preferably the human factor Xa.
- the method and reagent according to the invention enable rapid and reliable determination of the prothrombin.
- the method is characterized by its specificity because the factor Xa only detects normal prothrombin and not also PIVKA prothrombin.
- the activators used up to now do not have a specific effect.
- the addition of a standardized factor Xa preparation ensures that a sufficient amount of the activator is always present. It was very surprising that after the addition of all prothrombin, factor Xa quickly and completely converted to thrombin without, which is very important, itself participating in the color reaction in any way. It is known that the factor Xa z. B. on synthetic peptide-p-nitroanilide derivatives, such as. B. Chromozym TH acts directly cleaving.
- the human factor Xa can be used more advantageously than e.g. B. Bovine factor Xa. It has proven to be particularly advantageous to add factor Xa in a defined amount; the activation of factor Xa present in the blood plasma would lead to unsatisfactory results. Furthermore, it was surprising that an activator can be provided by a manufacturing process as simple as the process according to the invention, which guarantees the feasibility, in particular the technical usability, and could be sufficiently profitable with regard to the origin, namely the human plasma.
- Plasma Blood from healthy donors with an average age of 30 years, half of whom are women and men, is used to obtain the normal plasma. It contains 25 mM sodium citrate. After a first centrifugation for 15 min, 1500 g and room temperature, the plasma is subjected to a second one at 4 ° C for 30 minutes at 20,000 g. 1 ml / 30 m aqueous calcium chloride solution and 2 drops Echis carinatus venom (Sigma V 8250; basic solutions each 1 mg / ml water) are added per 4 ml normal plasma and left for about 2 hours in a water bath (37 ° C).
- Echis carinatus venom Sigma V 8250; basic solutions each 1 mg / ml water
- the resulting clot is centrifuged off and 150 mg of barium sulfate are added to the supernatant from 4 ml of normal plasma. The mixture is stirred at room temperature for 30 minutes and centrifuged. The supernatant is discarded and the precipitate is washed four times with about 4 ml of physiological saline. The centrifugate is eluted with 2 ml of a 0.2 M trisodium citrate solution (pH 7.0). After centrifugation again, the supernatant is dialyzed against physiological saline at 4 ° C. The dialysate is stored in small protions of approximately 250 ⁇ l at -20 ° C.
- Test mixtures are produced which contain:
- the phospholipids used are an acetone / ether extraction from a human brain according to W. N. Bell and H. G. Alton, Nature (London) 174, page 880 (1954).
- the components of the test mixture are pipetted directly into the microcuvette with a layer thickness of 1 cm of a "Aminco DW 2" spectrophotometer at 37 ° C.
- the incubation time for factor Xa is 120 seconds.
- 50 ⁇ l (1.5 mM / I) substrate (Chromozym TH, Boehringer Mannheim GmbH, or substrate 2238, Kabi) are added, the final concentration being 187.5 ⁇ M / l (Chromozym TH) or 148 ⁇ M / l ( S 2238).
- the measurement begins immediately.
- the absorption per time is recorded directly with a pointer running speed in minutes per cm in the horizontal and an absorption in mm per mm full scale in the vertical.
- Various absorption sensitivities and running speeds can be selected.
- the absorption change per minute is therefore calculated using the following formula: Example for measuring distance 10 cm, vertical 43 mm full scale 252 mm, absorption sensitivity 0.5 and running speed 0.033:
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Health & Medical Sciences (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Biomedical Technology (AREA)
- General Engineering & Computer Science (AREA)
- Analytical Chemistry (AREA)
- Neurosurgery (AREA)
- Physics & Mathematics (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE2757992 | 1977-12-24 | ||
DE19772757992 DE2757992A1 (de) | 1977-12-24 | 1977-12-24 | Verfahren zur prothrombin-bestimmung |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0003474A1 EP0003474A1 (de) | 1979-08-22 |
EP0003474B1 true EP0003474B1 (de) | 1981-11-25 |
Family
ID=6027271
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP78101680A Expired EP0003474B1 (de) | 1977-12-24 | 1978-12-14 | Verfahren zur Prothrombin-Bestimmung, dazu verwendetes Reagenz und Verfahren zur Herstellung eines Faktor-Xa-Präparats |
Country Status (9)
Country | Link |
---|---|
US (1) | US4334018A (no) |
EP (1) | EP0003474B1 (no) |
JP (2) | JPS588840B2 (no) |
AT (1) | AT360661B (no) |
CA (1) | CA1127942A (no) |
DE (2) | DE2757992A1 (no) |
DK (1) | DK150719C (no) |
FI (1) | FI64466C (no) |
NO (2) | NO151792C (no) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4289498A (en) * | 1979-01-08 | 1981-09-15 | Ortho Diagnostics, Inc. | One-stage prothrombin assay and compositions useful therein |
US4463090A (en) * | 1981-09-30 | 1984-07-31 | Harris Curtis C | Cascade amplification enzyme immunoassay |
DE3413311A1 (de) * | 1984-04-09 | 1985-10-17 | Behringwerke Ag, 3550 Marburg | Reagenz zur bestimmung der thromboplastinzeit |
GB2178533B (en) * | 1985-07-22 | 1989-07-19 | Asahi Chemical Ind | Analytical method of enzyme precursors and device therefor |
DE3607559A1 (de) * | 1986-03-07 | 1987-09-10 | Boehringer Mannheim Gmbh | Verfahren zur photometrischen bestimmung der protein c- und/oder protein s-aktivitaet |
US4937188A (en) * | 1986-04-15 | 1990-06-26 | Northeastern University | Enzyme activity amplification method for increasing assay sensitivity |
US5190864A (en) * | 1986-04-15 | 1993-03-02 | Northeastern University | Enzyme amplification by using free enzyme to release enzyme from an immobilized enzyme material |
JPS62278717A (ja) * | 1986-05-27 | 1987-12-03 | Nec Kansai Ltd | 直熱型陰極構体 |
US5312745A (en) * | 1987-06-18 | 1994-05-17 | Chromogenix Ab | Determination of components active in proteolysis |
DE3727610A1 (de) | 1987-08-19 | 1989-03-02 | Behringwerke Ag | Synthetische peptide, gegen diese gerichtete antikoerper und deren verwendung |
US6541275B1 (en) | 1988-02-03 | 2003-04-01 | Dade Behring Inc. | Immunoassay for F1.2 prothrombin fragment |
DE4203980A1 (de) * | 1992-02-11 | 1993-08-12 | Max Planck Gesellschaft | Verfahren zur bestimmung von hirudin und synthetischen thrombininhibitoren |
AT396937B (de) * | 1992-04-06 | 1993-12-27 | Immuno Ag | Verfahren zur aktivierung von blutgerinnungsfaktoren |
US5780255A (en) * | 1995-06-09 | 1998-07-14 | Instrumentation Laboratory, S.P.A. | Protein C pathway screening test |
DE102010025972A1 (de) * | 2010-07-02 | 2012-01-05 | Papst Licensing Gmbh & Co. Kg | Verfahren zur Bestimmung von Proteasen und ihren Proformen |
EP3253870B1 (en) * | 2015-02-06 | 2021-06-23 | Guangzhou Bioseal Biotech Co., Ltd. | Method for preparation of thrombin |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3486981A (en) * | 1965-03-15 | 1969-12-30 | Roy E Speck | Substances relating to testing of blood-coagulation |
SE380257B (sv) * | 1972-05-02 | 1975-11-03 | Bofors Ab | Nya diagnostiskt verksamma substrat med hog specificitet till trombin och andra proteolytiska enzymer av typen peptidyl-peptid-hydrolaser |
ES431736A1 (es) * | 1973-11-13 | 1977-05-16 | Behringwerke Ag | Procedimiento para la preparacion de un agente para diagnos-tico para el proposito de efectuar el control de la capaci- dad de coagulacion de la sangre. |
CH622286A5 (no) * | 1975-06-23 | 1981-03-31 | Pentapharm Ag | |
US4061625A (en) * | 1975-07-11 | 1977-12-06 | Ab Kabi | Novel chromogenic thrombin substrates |
SE407405B (sv) * | 1975-07-11 | 1979-03-26 | Kabi Ab | Nya kromogena trombinsubstrat |
SE419871B (sv) * | 1975-12-01 | 1981-08-31 | Pharmacia Ab | Sett att bestemma aktiviteten hos faktor xa-inhibitor i blod |
-
1977
- 1977-12-24 DE DE19772757992 patent/DE2757992A1/de not_active Withdrawn
-
1978
- 1978-12-14 DE DE7878101680T patent/DE2861386D1/de not_active Expired
- 1978-12-14 EP EP78101680A patent/EP0003474B1/de not_active Expired
- 1978-12-18 FI FI783880A patent/FI64466C/fi not_active IP Right Cessation
- 1978-12-20 DK DK571978A patent/DK150719C/da not_active IP Right Cessation
- 1978-12-21 JP JP53156954A patent/JPS588840B2/ja not_active Expired
- 1978-12-21 NO NO784318A patent/NO151792C/no unknown
- 1978-12-22 AT AT924378A patent/AT360661B/de not_active IP Right Cessation
- 1978-12-22 CA CA318,481A patent/CA1127942A/en not_active Expired
-
1980
- 1980-12-15 US US06/216,696 patent/US4334018A/en not_active Expired - Lifetime
-
1981
- 1981-05-22 JP JP56076831A patent/JPS5812257B2/ja not_active Expired
-
1983
- 1983-10-25 NO NO83833884A patent/NO154803C/no unknown
Also Published As
Publication number | Publication date |
---|---|
FI64466B (fi) | 1983-07-29 |
DE2861386D1 (en) | 1982-01-28 |
JPS588840B2 (ja) | 1983-02-17 |
DK150719C (da) | 1988-06-06 |
NO154803C (no) | 1986-12-29 |
JPS5492393A (en) | 1979-07-21 |
DK150719B (da) | 1987-06-01 |
DK571978A (da) | 1979-06-25 |
NO154803B (no) | 1986-09-15 |
EP0003474A1 (de) | 1979-08-22 |
NO151792B (no) | 1985-02-25 |
CA1127942A (en) | 1982-07-20 |
JPS5812257B2 (ja) | 1983-03-07 |
FI64466C (fi) | 1983-11-10 |
NO151792C (no) | 1985-06-05 |
US4334018A (en) | 1982-06-08 |
FI783880A (fi) | 1979-06-25 |
DE2757992A1 (de) | 1979-06-28 |
NO784318L (no) | 1979-06-26 |
AT360661B (de) | 1981-01-26 |
JPS5718626A (en) | 1982-01-30 |
ATA924378A (de) | 1980-06-15 |
NO833884L (no) | 1979-06-26 |
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